Mema

• Drugs that act on the central nervous system (CNS) are the most commonly prescribed drugs in current use
• Most of these drugs act by changing ion flow through transmembrane channels of nerve cells
• Transmitter reuptake transporters constitute a second class of drug targets, especially for antidepressant agents
• A few drugs appear to act by altering the function of neuroglia
• Neurons


  • Electrically excitable cells that process and transmit information via an electrochemical process
  • Soma (Body) - integrated incoming signal from dendrites
  • Dendrites - tree-like projection that receives information
  • Axon - passes the signal from dendrite to the next cell
  • Synapse - gaps between 2 cells where passage of information happens
• Neuroglia


  • Astrocytes - main supporting cell that remove excess neurotransmitter; serves as fuel reserve to destroy glycogen; a component of BBB
  • Oligodendrocytes – forms myelin sheath in CNS; same function w/ Schwann cells
  • Schwann cell – forms myelin sheath in neurons of PNS
  • Microglia – macrophages in CNS
  • Ependymal cells - helps produce cell cerebrospinal fluid
• Blood-Brain Barrier (BBB)


  • Protective separation of the circulating blood from the extracellular fluid of the CNS that limits the penetration of substances
  • Tight junctions between the capillary endothelial cells, base membrane, astrocyte end-feet
  • Tightly packed capillary endothelial cells
  • Basement membranes
  • Astrocyte foot processes

  
• Only LUNA can pass the BBB
• Voltage-gated channels


  • Responds to changes in the (plasma) membrane potential
  • Highly concentrated in the initial segment of the axon
  • Initiates all-or-nothing action potential
• Ligand-gated channels


  • Aka ionotropic receptors
  • Neurotransmitter receptor
  • Respond to the binding of ligand that will trigger the opening of the channel
• Metabotropic receptors


  • Neurotransmitter receptor
  • GPCR
  • Binding of NTM to the receptor triggers the dissociation of a from beta-gamma subunit
  • Βγ subunit activation of voltage-gated channels (Ca2+ & K+ channels)
  • Can also generate diffusible secondary messengers

  
• 2 Main types of receptor

  • Ionotropic receptors
  • Metabolic receptors
• Synapse


  • Specialized gap region between 2 opposing cell membranes
  • Communication between neurons in the CNS occurs through chemical synapses in majority of cases (some are electrical)
  • Electrical synapse – electrical continuity between cells
  • Chemical synapses – NTM
• Synaptic transmission


  1. Action potentials propagating down the axon activates voltage-sensitive Ca2+ channels

  2. Increase in intracellular calcium promotes the fusion of synaptic vesicles with the presynaptic membrane

  3. Neurotransmitter(NTM) are released in the synaptic cleft and diffuses on the postsynaptic membrane

  4. NTM binds to a receptor and opens a channel (directly or indirectly) → postsynaptic event or response
• Excitatory (depolarizing) postsynaptic potentials (EPSP)


  • Usually generated by the opening of Na+ or Ca2+ channels
  • Closing of K+ channels
• Inhibitory (hyperpolarizing) postsynaptic potentials (IPSP)

  Generated by opening of K+ or Cl- channels
• Site of drug action

  • A small number of neuropharmacological drugs exert their effects in the axon
  • Most therapeutically important CNS drugs acts mainly on the synapses
• Sites of CNS drug action

  • Drugs may alter: the action potential in the presynaptic fiber
  • synthesis of transmitter
  • storage
  • metabolism
  • release
  • reuptake
  • degradation
  • receptor for the transmitter
  • receptor-induced decrease or increase in ionic conduction
• Hierarchical systems


  • Includes all the pathways directly involved in sensory perception & motor control
  • Delimited in their distribution
  • Contains large, myelinated, rapidly conducting fibers (transfer information rapidly)
• 2 Types of cells

  • Projection/Relay Neurons - Excitatory neurons (Glutamate & Aspartate)
  • Local Circuit Neurons - Most are inhibitory neurons (GABA & Glycine)
• Diffuse neuronal system


  • Broadly distributed
  • Fine, unmyelinated, and conduct very slowly
  • Monoamines & Acetylcholine

  
• Criteria for transmitter status

  • Present in a higher concentration in the synaptic area than in other areas
  • Released by electrical or chemical stimulation via a calcium-dependent mechanism
  • Produce the same sort of postsynaptic response that is seen with activation of the synapse
• Acetylcholine


  • First compound to be identified pharmacologically as NTM in the CNS
  • Most CNS responses to Ach are mediated by M1 receptors → Excitation

  
• Drugs affecting the activity of cholinergic systems in the brain

  • Acetylcholinesterase inhibitors used of Alzheimer's disease (Rivastigmine)
  • Antimuscarinic agents for Parkinsonism (Benztropine)

  
• Monoamine neurotransmitters


  • Monoamine include the catecholamines (Da & NE) and 5-HT
  • Dopamine (Da) - Dopaminergic pathways include the Nigrostriatal, Mesolimbic, Mesocortical, and Tuberoinfundibular
  • Norepinephrine (NE) - Most of the NE neurons are located in the locus coeruleus (brain stem) or lateral tegmental area of pons
  • Serotonin (5-HT) - Originates in the midline raphe nuclei of pons and upper brain stem

  
• Diamine neurotransmitters


  • Related to Monoamine NTM; very small amount in CNS
  • Histamine - Tuberomammillary nucleus in the posterior hypothalamus

  
• Amino acid neurotransmitters


  • Glutamate - Major excitatory NTM in the brain
  • GABA - Major inhibitory NTM in the brain
  • Glycine - Major inhibitory NTM in the spine

  
• Peptide transmitters


  • Packaged in large, dense cores and synthesized in cell body
  • No reuptake mechanisms
  • Opioid peptides - Therapeutic actions of opioid analgesics are mediated via activation of endogenous peptide receptors
  • Substance P - Nociceptive sensory pathway
  • Orexins - Associated with sleep-wake cycle & promote wakefulness
• Endocannabinoids


  • Primary psychoactive ingredient of cannabis (Δ9-tetrahydrocannabinol (Δ9-THC), affects the brain by activating CB1 receptor
  • Ligands are not stored but are rapidly synthesized
  • May affect memory, cognition, and perception
• Sedative hypnotics belong to a chemically heterogenous class of drugs, almost all causes a dose-dependent CNS depressant effects
• Sedation (anxiolytic)


  Relief of anxiety; calming effect
• Hypnosis


  Produces drowsiness & encourage sleep & maintenance of state of sleep
• Sedative-hypnotics cause a graded dose-dependent depression of the CNS
• Opioid peptides


  • beta-endorphin
  • met-enkephalin
  • leu-enkephalin
  • dynorphin
• Therapeutic actions of opioid analgesics

  Mediated via activation of endogenous peptide receptors
• Substance P


  Nociceptive sensory pathway
• Orexins


  Associated with sleep-wake cycle & promote wakefulness
• Endocannabinoids


  Primary psychoactive ingredient of cannabis (Δ9-tetrahydrocannabinol (Δ9-THC)), affects the brain by activating CB1 receptor
• Ligands are not stored but are rapidly synthesized
• May affect memory, cognition, and perception